In most cases of Alzheimer's diseased (AD), it is impossible to identity the triggering event which leads to the neurodegenerative process. However, in a small subset (2-3%) of familial Alzheimer disease (FAD) kindreds, several mutations have been found in a chromosome 21 gene, APP encoding the precursor of the Abeta peptide that is deposited in amyloid plaques. Detailed family studies have shown that AD is genetically heterogeneous and linkage studies using markers from other chromosomes have led to the localization of a late-onset (more 65 years) FAD locus mapping within or close to the APOE gene on chromosome 19. More recently, the extended FAD pedigree collections made possible through the efforts of the Massachusetts ADRC over the past ten years have allowed our laboratory in collaboration to localize a major FAD locus on chromosome 14. Among the FAD pedigrees screened in our Boston-Toronto study, six independent pedigrees individually yielded lod scores exceeding the conventional significance value of 3. The magnitude and robustness of these scores indicate definitively that there is a chromosome 14 locus that most likely accounts for a major proportion (70-90%) of early-onset FAD (lessor 65 years). The goal of this proposal is to employ a variety of strategies including positional cloning, physical mapping, and testing of candidate genes to ultimately isolate, identify, and characterize the FAD gene defect on chromosome 14. Given our extensive collection of well characterized early-onset FAD pedigrees and the large amount of preliminary data that we have already amassed concerning the chromosome 14 FAD locus, we are in a uniquely ideal position to successfully carry out the studies described in this application. The knowledge obtained from the proposed studies could provide critical clues to the causes of both inherited and sporadic AD, and ultimately provide vital information for designing treatments aimed at strategically intervening with the effects of discovered FAD gene defects.